STIMULATION OF CD40 WITH PURIFIED SOLUBLE GP39 INDUCES PROINFLAMMATORY RESPONSES IN HUMAN MONOCYTES

CD40 is a glycoprotein of about 50 kDa that plays a crucial role in B cell growth and differentiation. It is found on the surface of B cells , follicular dendritic cells, monocytes, and some endothelial, epithel ial, and carcinoma cells. Engagement of CD40 with anti-CD40 mAbs, gp39 expressed on the cell surface or soluble forms of gp39, primes B cell s to efficiently respond to subsequent stimulatory signals leading to B cell proliferation, differentiation, and isotype switching. Peripher al monocytes also express CD40 on the cell surface and expression is i ncreased following treatment with IFN-gamma. Using a soluble murine CD 8/human gp39 fusion protein (sgp39) we have found that CD40 plays a cr ucial role in the regulation of monocyte function. Stimulation of huma n peripheral monocytes with sgp39 induced homotypic aggregation and si gnificantly increased the expression of several cell-surface proteins including CD54, MHC class II, CD86, and CD40. Soluble gp39 also dramat ically enhanced monocyte survival, preventing the onset of apoptosis t hat normally occurs upon withdrawal of serum. Finally, in the absence of any costimulatory molecules, sgp39 stimulated monocytes to produce TNF-alpha, IL-1 beta, IL-6, and IL-8. These results suggest that ligat ion of CD40 on human monocytes induces phenotypic changes that would b e expected to influence T cell activation by the monocyte and also to enhance or prolong inflammatory responses.